Halogen-lithium exchange mechanism

If 3-bromothiophene is added to butyllithium at a sufficiently low rate, no 2-lithio-thiophene is formed, because the halogen-lithium exchange is much faster than the vicinal metallation of the bromo compound. Support for the mechanism of trans-metallation was provided by adding an equivalent amount of thiophene to a solution of 3-lithiothiophene in THF, cooled at —30 °C after 1.5 h only the 2-lithio derivative was present in the solution [9]. In Et20 this trans-metallation was very slow. 

Despite its apparent simplicity, the halogen-lithium exchange reaction remains mechanistically intriguing. - Depending on the substrate and conditions, halogen-lithium exchange may involve a four-center transition State, radical intermediates via a single-electron transfer (SET) mechanism, or a nucleophilic mechanism perhaps via an "ate"... 

Schlosser and co-workers have reported the shift of lithium in lithiated l-bromo-3-(tri-fluoromethyl)benzene 2,fa Quenching at — 100 C gives exclusively the product derived from 2, whereas after 2 hours at — 75 C, arene 2 is completely converted into less basic 3. A lithium-iodine exchange takes place in lithiated 2-chloro-3-iodo-6-(trifluoromethyl)pyridine 4, which at —85 C is totally converted into the less basic isomer 5.7 These rearrangements have been discussed in terms of a base-catalyzed halogen dance or halogen-shuffling mechanism. 

A reaction similar to the overall copper-halogen exchange observed on addition of perhaloarenes to lithium dimethylcuprate is also given by pentafluorobenzene, pentachlorobenzene, 2,3,5,6-tetrachloropyridine (146), and tetrafluorobenzenes (144). A small excess of methyllithium was again required, otherwise the reactions were very slow. Formation of methylcopper during the addition was not observed with the poly-fluoroarenes, but a mechanism was proposed similar to that for the perhaloarenes (146). Equation (22) represents the overall reaction for pentafluorobenzene. In most cases, methane was evolved nearly quantitatively. 

This mechanism has been confirmed using isotopically labelled fluorobenzene. Benzynes have been trapped by dienes in Diels-Alder reactions. They can also be generated by strong bases such as sodium amide in liquid ammonia in this way bromobenzene can be used without the interference of metal-halogen exchange which is the preferred course with lithium alkyls. 

The chemistry of alkenyl- and alkyl-substituted cyclopropylidenes has been explored. They were generated from a. gm-dihalide by lithium-halogen exchange, and were shown to give both allenes and 1,5-CH bond insertion reactions. A new mechanism for the insertion of carbenes into OH bonds was proposed on the basis of a computational study. A cyclic five-membered transition state, composed of the car-bene and two hydroxyl-containing molecules, was shown to be lower in energy than proton transfer or direct insertion into an OH bond. ... 

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